The present invention generally relates to quorum sensing and specifically relates to methods for modulating bacterial quorum sensing using antagonist or agonist compounds, and to methods of treating or preventing microbial damages and diseases, in particular for diseases where there is an advantage in inhibiting quorum sensing regulated phenotypes of pathogens.
Many microbial pathogens cause tremendous damages worldwide, in humans as well as in animals and crop plants. The continuing emergence of multiple-drug-resistant pathogen strains has necessitated finding new compounds that can be used in antimicrobial treatment. In general, two strategies exist for controlling the pathogens: either to kill the pathogen or to attenuate its virulence such that it does not cause damages to the host.
The latter approach has the advantage of not creating selective pressure in favor of drug resistant strains. Antimicrobial compounds having virulence—attenuating but not cell-killing effects are expected to remain effective for longer period of time than conventional antibiotics because of the lack of development of drug resistance. This approach has, however, suffered from a lack of specific targets for rational drug design.
The bacterial quorum-sensing regulatory system offers such a novel target. The control of gene expression in response to cell density, or quorum sensing, was first described in the marine luminous bacteria Vibrio fischeri and Vibrio harveyi. This phenomenon has recently become recognized as a general mechanism for gene regulation in many Gram negative bacteria. Quorum sensing bacteria synthesize, release, and respond to specific acyl-homoserine lactone (“AHL” or “HSL”) signaling molecules called autoinducers (“AI”) to control gene expression as a function of cell density.
Except that of V. harveyi, all acyl-homoserine lactone quorum sensing systems described to date utilize an autoinducer synthase encoded by a gene homologous to luxl of V. fischeri, and response to the autoinducer is mediated by a transcriptional activator protein encoded by a gene homologous to luxR of V. fischeri (Bassler and Silverman, in Two component Signal Transduction, Hoch et al., eds, Am. SOC. Microbiol. Washington D.C., pp 431-435, 1995).
V. harueyi has two independent density sensing systems (Signaling Systems 1 and 2), and each is composed of a sensor-autoinducer pair. Signaling System 1 is composed of Sensor 1 and autoinducer 1 (AI-1), which is N(3-hydroxybutanoyl)-L-homoserine lactone (see Bassler et al., Mol. Microbiol. 9: 773-786, 1993). Signaling System 2 is composed of Sensor 2 and autoinducer 2 (AI-2) (Bassler et al., Mol. Microbiol. 13: 273-286, 1994). Signaling System 1 is a highly specific system proposed to be used for intra-species communication and Signaling System 2 appears to be less species selective, and is hypothesized to be for inter-species communication (Bassler et al., J. Bacteriol. 179: 4043-4045, 1997).
In recent years it has become apparent that many Gram negative bacteria employ one or more quorum sensing systems comprising HSL derivatives with different acyl side chains to regulate in a cell-density dependent manner a wide variety of physiological processes such as swarming motility, biofilm formation, pathogenicity, conjugation, bioluminescence or production of pigments and antibiotics (for reviews and references see, e.g.: Fuqua et al., 1996, Ann. Rev. Microbiol. 50:727-51; Fuqua et al., 1998, Curr. Opinion Microbiol. 1:183-89, 1998; Eberl, 1999, Syst. Appl. Microbiol. 22:493-506; and De Kievit et al., 2000, Infect. Immun. 68:4839-49).
The quorum sensing system is an attractive antibacterial target because it is not found in humans and is critical for high level bacterial virulence. Targeting quorum sensing could have far reaching implications for treatment of many human pathogens that use quorum sensing virulence regulation, such as species of Bordetella, Enterobacter, Pseudomonas aeruginosa, Serratia, and Yersinia. 
Recent studies in vivo have shown that the virulence of Pseudomonas aeruginosa lacking one or more genes responsible for quorum sensing is attenuated in its ability to colonize and spread within the host. Similarly, elimination of the AHL synthase in several plant pathogenic bacteria has lead to complete loss of infectivity (Beck von Bodman, 1998, Proc. Natl. Acad. Sci. USA 95:7687-7692; Whitehead et al., 2001, Microbiol. Rev. 25:365-404). Moreover, ectopic expression of AHL synthases in transgenic plant systems has demonstrated that when invading bacteria encounter inducing levels of AHLs, their behaviors are sufficiently modulated to shift the delicate balance of host-microbe interactions in favor of disease resistance (Fray et al., 1999, Nat. Biotechnol. 171:1017-1020; Mae et al., 2001, Mol. Plant Microbe Interact. 14:1035-1042). A number of plants, including common crop plants, produce endogenous AHL-mimic compounds, and it is thought that these AHLs are the basis of varying degrees of disease resistance and susceptibility (Teplitski et al., 2000, Mol. Plant Microbe Interact. 13:637-648). In addition, the halogenated furanones produced by some marine algae are known to have a pronounced effect on suppressing marine biofouling.
Nevertheless, currently there are no antibacterial compounds that target bacterial quorum sensing system to reduce bacterial virulence and increase susceptibility to bactericidal antibiotics. Accordingly, it is an objective of the present invention to provide newly identified novel compounds that are antagonists or agonists of bacterial quorum sensing. The present invention further provides methods of modulating bacterial quorum sensing, and methods of treating or preventing bacterial infection using the novel antagonists and agonists of the present invention.